Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Processes of preparing a desired or intentional composition...
Reexamination Certificate
2001-12-04
2004-10-05
Szekely, Peter (Department: 1714)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Processes of preparing a desired or intentional composition...
C523S111000, C523S124000, C524S610000, C528S356000, C528S359000, C528S400000, C623S001210, C424S078080, C424S486000
Reexamination Certificate
active
06800672
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biodegradable poly(phosphoester) compositions that degrade in vivo into non-toxic residues, in particular those containing a cycloaliphatic structure in the polymer backbone. The compositions of the invention are particularly useful as flexible or flowable materials for localized, controlled drug delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant applications. If a medical implant is intended for use as a drug delivery or other controlled-release system, using a biodegradable polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al.,
“Chemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agents”, J. Macro. Science, Rev. Macro. Chem. Phys.
, C23(1), 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. Polymers have been used for some time as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., “Polymeric Controlled Drug Delivery”,
Advanced Drug Delivery Rev.,
1:199-233 (1987); Langer, “New Methods of Drug Delivery”,
Science,
249:1527-33 (1990) and Chien et al.,
Novel Drug Delivery Systems
(1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.
When a non-biodegradable polymer matrix is used, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is normally longer for a non-biodegradable matrix than for a biodegradable matrix, for which passage through the channels of the matrix, while it may occur, is no longer required.
Since many pharmaceuticals have short half-lives, therapeutic agents can decompose or become inactivated within the non-biodegradable matrix before they are released. This issue is particularly significant for many bio-macromolecules, e.g., proteins and smaller polypeptides, since these molecules are generally hydrolytically unstable and have markedly low permeabilities through most polymer matrices. In non-biodegradable matrices, many bio-macromolecules even begin to aggregate and precipitate out of solution, blocking the very channels necessary for diffusion out of the carrier matrix.
These problems are alleviated somewhat by using a biodegradable rigid matrix that, in addition to some diffusional release, primarily allows the controlled release of the therapeutic agent by degradation of the solid polymer matrix. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., “Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonists”,
Controlled Release of Bioactive Materials,
19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. “Trends in the Development of Bioresorbable Polymers for Medical Applications”,
J. Biomaterials Appl.,
6:1, 216-50 (1992); polyurethanes (Bruin et al., “Biodegradable Lysine Diisocyanate-based Poly(Glycolide-co-&egr; Caprolactone)-Urethane Network in Artificial Skin”,
Biomaterials,
11:4, 291-95 (1990); polyorthoesters (Heller et al., “Release of Norethindrone from Poly(Ortho Esters)”,
Polymer Engineering Sci.,
21:11, 727-31 (1981); and polyanhydrides (Leong et al., “Polyanhydrides for Controlled Release of Bioactive Agents”,
Biomaterials
7:5, 364-71 (1986).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al.,
Handbook of Polymer Synthesis
, Chapter 17: “Phosphorus-Containing Polymers”, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows:
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or R′ group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with —O-carboxy groups may be coupled to the phosphorus via a phosphoester bond, which is hydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. The P-O-C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
However, drug-delivery systems using most of the known biodegradable polymers, including those of phosphoesters, have been rigid materials. In such instances, the drug is incorporated into the polymer, and the mixture is shaped into a certain form, such as a cylinder, disc, or fiber for implantation.
However, proteins and other large biomolecules are still difficult to deliver from rigid biodegradables because these larger molecules are particularly unstable and are typically degraded along with the solid polymeric matrix carrier. More specifically, when a polymer begins to degrade following administration, a highly concentrated microenvironment is created from the breakdown by-products of the polymer as the polymer becomes ionized, protonated or hydrolyzed. Proteins are easily denatured or degraded under these conditions and then are useless for therapeutic purposes.
Further, in the process of preparing rigid drug delivery systems, biologically active substances such as proteins are commonly exposed to extreme stresses. Necessary manufacturing steps may include excessive exposure to heat, pH extremes, large amounts of organic solvents, cross-linking agents, freezing and drying. Following manufacture or preparation, the drug delivery systems must be stored for some extended period of time prior to administration, and little information is available on the subject of long term stability of proteins within solid biodegradable delivery systems.
Rigid polymers can be inserted into the body with a syringe or catheter in the form of small particles, such as microspheres or microcapsules. However, because they are still solid particles, they do not form the continuous and nearly homogeneous, monolithic matrix that is sometimes needed for preferred release profiles.
In addition, microspheres or microcapsules prepared from these polymers and containing biologically active substances to be released into the body are sometimes difficult to produce on a large scale. Most of the microencapsulation processes involve high temperature and contact with organic solvents, steps that tend to damage the bioactivity of proteins. Moreover, their storage often presents problems and, upon injection, their granular nature can cause blockages in injection devices and/or irritation of the soft tissues into which the small particles are injected.
Dunn et al., U.S. Pat. Nos. 5,278,201; 5,278,202; and 5,340,849, disclose a thermoplastic drug delivery system in which a solid, linear-chain, biodegradable polymer or copolymer is dissolved in a solvent to form a liquid solution. Once the polymer solution is placed i
Dang Wenbin
English James P.
Kadiyala Irina
Leong Kam W.
Mao Hai-quan
Foley & Hoag LLP
Guilford Pharmaceuticals Inc.
Szekely Peter
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